m6A修饰介导的谷氨酰胺酶可变剪接体转换驱动结直肠癌进展和转移的研究

结直肠癌作为消化道恶性肿瘤的一种，在我国呈现高发态势，每年新 增患者数量约为 55 万例，为经济社会的发展带来了巨大的负担。转移是造 成结直肠癌患者死亡的主要原因，转移性结直肠癌往往不可彻底清除且普 遍耐药，这为肿瘤临床治疗带来了巨大的困难。肿瘤的转移和耐药伴随着 肿瘤细胞的代谢重编程。在本研究中我们发现，转移性结直肠癌细胞高度 依赖于谷氨酰胺的摄取，谷氨酰胺酶 GLS1 在结直肠癌中高表达，且由低活 性的 KGA 亚型转换为高活性的 GAC 亚型，GLS1 的剪接亚型从 KGA 到 GAC 的转换可以促进结直肠癌的进展和转移，敲低 GAC 能够有效抑制结直 肠癌的转移。同时我们发现 m6A 修饰介导的可变剪接是 GLS1 两种亚型间 转换的主要原因，其中 Mettl3 作为 m6A 甲基转移酶，能够参与修饰高活性 转录本 GAC 独有外显子上的 m6A 位点，直接调控 GLS1 的可变剪接，促使 KGA 亚型向 GAC 亚型的转换。于此同时，我们发现 GAC 和 KGA 的 PSI （percent-splice-in）相对表达水平，即 GAC/KGA 比值能够作为新的肿瘤标 志物，为多种癌症预测肿瘤的发生，有效分类肿瘤 T 分期以及精确评估患 者生存预后。总之，我们证明 Mettl3 可通过调控 KGA 向 GAC 亚型转换驱 动结直肠癌的转移和侵袭，为预防结直肠癌转移和治疗转移性结直肠提供 有潜力的靶点，GAC 和 KGA 的 PSI（percent-splice-in）相对表达水平在临 床中的应用潜力能够为多种癌症患者提供更为精准的治疗方案。

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